PROJECT SUMMARY Estrogen is an important hormone in energy balance and body weight. Low circulating estrogen levels have been linked to metabolic dysfunction, obesity and cardiovascular disease in women. As such, a better understanding of estrogen?s role in mediating energy expenditure is needed. Recent studies published by others have demonstrated that estrogen regulates brown adipose tissue (BAT)-induced thermogenesis and energy expenditure by acting on neurons in the ventromedial hypothalamus (VMH). Studies from our lab have discovered a subpopulation of ER?-enriched VMHvl neurons that regulate energy expenditure primarily in females. I hypothesize that central estrogen signaling acting on ER? enriched VMHvl neurons directly affects BAT thermogenesis in females. In Aim 1 I will ask if estrogen activation of VMHvl neurons increases BAT thermogenesis in female mice by direct stereotaxic injection of estradiol benzoate (EB) into the VMHvl. Also I will ask if activation of ER? VMHvl neurons by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) delivered into the VMHvl directly stimulates BAT thermogenesis in females. In Aim 2 I will ask if acute ablation of ER? signaling in the VMHvl decreases BAT thermogenesis in females. I will accomplish these aims by leveraging my new reporter transgenic mouse line that expresses luciferase under control of uncoupling protein 1 (Ucp1), referred to in the text as CH-TM mice. Together, these aims should begin to establish how estrogen signaling in the VMH controls BAT thermogenesis and energy balance, specifically in females.